Use of 5␣-Reductase Inhibitors for Prostate Cancer
Chemoprevention: American Society of Clinical Oncology/
American Urolog...
prevention, a strong area of research, is particularly
relevant to practicing oncologists and urologists be-
cause its app...
multidisciplinary process, review of evidence, and
documentation. Guidelines may be useful in produc-
ing better care and ...
members and with drafting the clinical questions the
Panel was to address. In August 2006 the entire Panel
met; the Panel ...
change. Finasteride is ineffective for relief of lower
urinary tract obstructive symptoms in patients who
do not have enla...
ment versus controls was 0.74 (95% CI, 0.56 to 0.98),
for an absolute risk reduction of 2.9% (9.2% v 6.3%;
Fig 2).
The PCP...
None of the trials was large enough to detect
clinically important differences in either prostate
cancer-specific mortality...
ticing physicians, and the Panel all struggled with
the question of whether the increase in high-grade
cancers reflected a ...
PCPT, and the theoretical possibility of increased
risk of prostate cancer mortality, should be dis-
cussed with these men...
In conclusion, a consistently uniform scale multi-
plier is currently unavailable because of inter- and
intraindividual va...
whether a shorter duration of a 5-ARI prevents
prostate cancer.
What are the future directions of research regard-
ing 5-A...
of three cases of high-grade cancer after approxi-
mately 7 years of therapy.
Men also should be informed that no informat...
need for surgical intervention. Harms include sexual
adverse effects, which usually diminish with time.
AUTHOR CONTRIBUTIO...
TABLE A2 (continued)
Study (references) and
Interventions (dose/d)
No. of
Randomly
Assigned
Patients
Treatment
Duration
(y...
TABLE A3
Period Prevalence of Prostate Cancer According to Subgroup
Subgroup/Reference
5-␣-Reductase Inhibitor Placebo
Rel...
11. Klein EA, Tangen CM, Goodman PJ, et al: Assessing
benefit and risk in the prevention of prostate cancer:
The prostate c...
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  1. 1. Use of 5␣-Reductase Inhibitors for Prostate Cancer Chemoprevention: American Society of Clinical Oncology/ American Urological Association 2008 Clinical Practice Guideline Barnett S. Kramer, Karen L. Hagerty, Stewart Justman, Mark R. Somerfield, Peter C. Albertsen,* William J. Blot, H. Ballentine Carter, Joseph P. Costantino, Jonathan I. Epstein, Paul A. Godley,† Russell P. Harris, Timothy J. Wilt, Janet Wittes,‡ Robin Zon and Paul Schellhammer§ From the National Institutes of Health, Bethesda, MD; American Society of Clinical Oncology, Alexandria, VA; University of Montana Liberal Studies, Missoula, MT; University of Connecticut Health Center, Farmington, CT; International Epidemiology Institute, Rockville, MD; Johns Hopkins University, Baltimore, MD; National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA; University of North Carolina at Chapel Hill, Chapel Hill, NC; University of Minnesota School of Medicine, Minneapolis, MN; Statistics Collaborative,Washington, DC; Michiana Hematology Oncology, Granger, IN; and Eastern Virginia Medical School, Norfolk, VA Approved by the American Society of Clinical Oncology Board on July 21, 2008, and by the American Urological Association Board on Octo- ber 17, 2008. This document is being reprinted as sub- mitted without editorial or independent peer review by the Editors of The Journal of Urology®. This guideline was developed through a col- laboration between the American Society of Clin- ical Oncology and the American Urological Asso- ciation, and has been published jointly by invitation and consent in the Journal of Clinical Oncology and The Journal of Urology®. No part of this document may be reproduced or transmit- ted in any form or by any means, electronic or mechanical, including photocopy, recording or any information storage and retrieval system, without written permission by the American So- ciety of Clinical Oncology or the American Uro- logical Association. * Financial interest and/or other relationship with GlaxoSmithKline. † Financial interest and/or other relationship with GlaxoSmithKline. ‡ Financial interest and/or other relationship with Merck. § Financial interest and/or other relationship with Theralogix, Dendreon Corporation, South- western Oncology Group and ContraVac. See Editorial on page 000. Purpose: To develop an evidence-based guideline on the use of 5-␣-reductase inhibitors (5-ARIs) for prostate cancer chemoprevention. Methods: The American Society of Clinical Oncology (ASCO) Health Services Committee (HSC), ASCO Cancer Prevention Committee, and the American Uro- logical Association Practice Guidelines Committee jointly convened a Panel of experts, who used the results from a systematic review of the literature to develop evidence-based recommendations on the use of 5-ARIs for prostate cancer che- moprevention. Results: The systematic review completed for this guideline identified 15 ran- domized clinical trials that met the inclusion criteria, nine of which reported prostate cancer period prevalence. Conclusion: Asymptomatic men with a prostate-specific antigen (PSA) Յ3.0 ng/mL who are regularly screened with PSA or are anticipating undergoing annual PSA screening for early detection of prostate cancer may benefit from a discussion of both the benefits of 5-ARIs for 7 years for the prevention of prostate cancer and the potential risks (including the possibility of high-grade prostate cancer). Men who are taking 5-ARIs for benign conditions such as lower urinary tract [obstructive] symptoms (LUTS) may benefit from a similar discussion, understanding that the improvement of LUTS relief should be weighed with the potential risks of high-grade prostate cancer from 5-ARIs (although the majority of the Panel members judged the latter risk to be unlikely). A reduction of approximately 50% in PSA by 12 months is expected in men taking a 5-ARI; however, because these changes in PSA may vary across men, and within indi- vidual men over time, the Panel cannot recommend a specific cut point to trigger a biopsy for men taking a 5-ARI. No specific cut point or change in PSA has been prospectively validated in men taking a 5-ARI. INTRODUCTION Surveys1,2 of American Society of Clinical Oncology (ASCO) members have shown strong interest in cancer prevention interventions applicable to clinical practice, and most respon- dents envision increased utilization of prevention in their practices. Chemo- 1642 www.jurology.com 0022-5347/09/1814-1642/0 Vol. 181, 1642-1657, April 2009 THE JOURNAL OF UROLOGY® Printed in U.S.A. Copyright © 2009 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2009.01.071
  2. 2. prevention, a strong area of research, is particularly relevant to practicing oncologists and urologists be- cause its application is well suited to the clinical setting in which shared decision making takes place between health professionals and individual pa- tients. To date, the strongest evidence of efficacy in the field of chemoprevention has come from the hor- monally responsive tumors: breast cancer with ta- moxifen and raloxifene3,4 and prostate cancer with the 5-␣-reductase inhibitor (5-ARI).5 Unlike most other chemopreventive agents under study, such as cyclooxygenase-2 inhibitors and retinoids, tamox- ifen and finasteride have been shown definitively in randomized clinical trials to decrease the incidence of invasive cancers—not just surrogate end points—in healthy people.3–6 Nevertheless, these agents have adverse effects that require careful dis- cussion with patients considering whether or not to take the agent. Although substantial data are available on the use of 5-ARIs in other settings—primarily, treat- ment of benign prostatic hyperplasia (BPH)7–10 — the Prostate Cancer Prevention Trial (PCPT) is the only completed randomized trial prospectively de- signed to show a reduction in period-prevalence of prostate cancer.5 The PCPT investigators reported a decrease in cumulative incidence of prostate cancer from 24.4% in the placebo arm to 18.4% in the fin- asteride arm during the 7 years of the trial. Never- theless, an observed increase of Gleason scores 7 to 10 in the finasteride study arm (37%, or 280 of 757 tumors) compared with the placebo arm (22.2%, or 237 of 1,068 tumors), noted in a secondary analysis, triggered concern about harm. These issues complicate informed decision mak- ing by patients who are considering finasteride for prostate cancer chemoprevention, and are impor- tant to the many men taking finasteride for the management of BPH or for male pattern baldness. Published proposals discuss the balance of risks and benefits of finasteride for the prevention of prostate cancer,11 although some have questioned the as- sumptions used in the calculation as overly favor- able.12 Because of the importance of the issue to both clinical oncologists and urologists, ASCO has collab- orated with the American Urological Association (AUA) to develop a clinical practice guideline on the benefits and harms of 5-ARIs for the prevention of prostate cancer. New information will likely become available from ongoing analyses in the PCPT and the results of the REDUCE (Reduction by Dutas- teride of Prostate Cancer Events) trial,13 a preven- tion trial testing dutasteride, which inhibits both isoforms (types 1 and 2) of 5-␣-reductase. This guide- line, sponsored by ASCO and AUA, aims to provide a useful tool for clinicians and their patients in making an informed decision about the potential harms and benefits of taking 5-ARIs for preventing prostate cancer. As part of its deliberations, the Panel also evaluated the outcomes of the PLESS (Proscar Long-Term Efficacy and Safety Study) and MTOPS (Medical Therapy of Prostatic Symptoms) trials, which examined 5-ARIs for the relief of uri- nary tract obstruction, because reduced incidence of urinary tract obstruction is one of the potential ben- efits of 5-ARI use. The charge to the Panel was to judge the balance of benefits and harms. GUIDELINE QUESTIONS This guideline addresses the use of 5-ARIs in pre- venting prostate cancer. The overarching question was should men routinely be offered a 5-ARI for the chemoprevention of prostate cancer? To address this question, the committee identified important compo- nents likely to influence assessments of the balance of risks and benefits and decision making that re- quired evaluation: 1. What is the impact of 5-ARIs on the risk of inci- dent prostate cancer, prostate cancer mortality, and overall mortality? Do benefits and harms of 5-ARIs vary among identifiable subpopulations (eg, age, race/ethnicity, family history, baseline risk for prostate cancer) and by type of 5-ARI? 2. Do 5-ARIs have a differential effect on the devel- opment of different histologic grades or stages of prostate cancer? Are any such differences likely to modify the curability of prostate cancer when diagnosed? Is the Gleason histologic grading sys- tem for prostate cancer applicable to men who are receiving 5-ARIs or other interventions that tar- get the androgen pathway? 3. What is the impact of 5-ARIs on the need for treatment of benign prostatic disease? 4. What is the impact of 5-ARIs on quality of life? What are other potential harms and adverse ef- fects of 5-ARIs? What are other potential benefits of, and indications for, 5-ARI use (eg, benign pros- tatic hyperplasia, male baldness)? 5. How long should treatment continue for the best outcome (period v lifelong)? 6. What are the future directions of research re- garding 5-ARIs for the prevention of prostate cancer? PRACTICE GUIDELINES Practice guidelines are systematically developed statements to assist practitioners and patients in making decisions about appropriate health care for specific clinical circumstances. Attributes of good guidelines include validity, reliability, reproducibil- ity, clinical applicability, clinical flexibility, clarity, 5␣-REDUCTASE INHIBITORS GUIDELINE 1643
  3. 3. multidisciplinary process, review of evidence, and documentation. Guidelines may be useful in produc- ing better care and decreasing cost. Specifically, uti- lization of clinical guidelines may provide the follow- ing: 1. Improvement in outcomes 2. Improvement in medical practice 3. Means for minimizing inappropriate practice variation 4. Decision support tools for practitioners 5. Points of reference for medical orientation and education 6. Criteria for self-evaluation 7. Indicators and criteria for external quality re- view 8. Assistance with reimbursement and coverage decisions 9. Criteria for use in credentialing decisions 10. Identification of areas where further research is needed. In formulating recommendations for the use of 5-ARIs for prostate cancer prevention, ASCO and AUA have considered these tenets of guideline de- velopment, emphasizing review of data from appro- priately conducted and analyzed clinical trials. These same tenets can be utilized and applied to formulation of prevention guidelines. However, it is important to note that guidelines cannot always ac- count for individual variation among patients. Guidelines are not intended to supplant physician judgment with respect to particular patients or spe- cial clinical situations and cannot be considered in- clusive of all proper methods of care or exclusive of other treatments reasonably directed at obtaining the same result. ASCO and AUA’s practice guidelines and technol- ogy assessments reflect expert consensus based on clinical evidence and literature available at the time they are written, and are intended to assist physi- cians in clinical decision making and identify ques- tions and settings for further research. Due to the rapid flow of scientific information in oncology, new evidence may have emerged since the time a guide- line or assessment was submitted for publication. Guidelines and assessments are not continually up- dated and may not reflect the most recent evidence. Guidelines and assessments cannot account for in- dividual variation among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It is the responsibility of the treating physician or other health care pro- vider, relying on independent experience and knowl- edge of the patient, to determine the best course of treatment for the patient. Accordingly, adherence to any guideline or assessment is voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient’s individual circumstances. ASCO and AUA guide- lines and assessments describe the use of procedures and therapies in clinical practice and cannot be as- sumed to apply to the use of these interventions in the context of clinical trials. ASCO and AUA assume no responsibility for any injury or damage to persons or property arising out of or related to any use of ASCO and AUA’s guidelines or assessments, or for any errors or omissions. METHODS Panel Composition The ASCO Health Services Committee (HSC) and the AUA Practice Guidelines Committee jointly convened an Expert Panel (hereafter referred to as the Panel) consist- ing of experts in clinical medicine and research methods relevant to chemoprevention for prostate cancer. The ex- perts’ fields included medical oncology, urology, pathology, epidemiology, statistics, and health services research. The Panel included academic and community practitioners as well as a patient representative. The Panel members are listed in Appendix Table A1. Literature Review and Analysis Wilt et al systematic review. The AUA commissioned a systematic review of the literature on the role of 5-ARIs in the chemoprevention of prostate cancer. That review, which is published in the Cochrane Library,14 served as the primary source of evidence for this guideline. Articles were selected for inclusion in the systematic review if they met the following prospective criteria: (1) a randomized controlled trial (RCT) that examined a 5-ARI versus a control; (2) treatment period that was at least 1 year; (3) study population that consisted of men age 45 years or older; (4) period prevalence of prostate cancer was one of the reported outcomes; and (5) the study was published after 1984. For nonprostate cancer outcomes, randomized trials were selected for inclusion if they met the following criteria: (1) treatment period was at least 6 months; (2) an RCT compared a 5-ARI to a nonactive control or to another active treatment; (3) study population consisted of men age 45 years or older; (4) at least one of the secondary outcomes of interest chosen by the Panel were reported; and (5) the study was published after 1999. This date was chosen because the AUA guideline on the management of BPH included studies published through 1999.7 PCPT authors provided unpublished information at the request of the panel. Additional details of the literature search strategy and meta-analyses are provided elsewhere.14 ASCO/AUA Expert Panel literature review and analy- sis. The Panel reviewed all data from the primary studies contained in the systematic review; subsequently, the Panel considered the results of the meta-analyses con- tained in the systematic review. Consensus Development Based on Evidence A steering committee met in October 2005. The steering committee was charged with identifying potential Panel 5␣-REDUCTASE INHIBITORS GUIDELINE1644
  4. 4. members and with drafting the clinical questions the Panel was to address. In August 2006 the entire Panel met; the Panel completed its additional work through teleconferences. The purposes of the Panel meeting were to refine the questions addressed by the guideline and to make writing assignments for the respective sections. All members of the Panel participated in the preparation of the draft guideline, which was then disseminated for re- view by the entire Panel. Feedback from external review- ers was also solicited. The ASCO HSC and the AUA Prac- tice Guidelines Committee, as well as the Board of Directors of both organizations, reviewed and approved the content of the guideline and the manuscript before dissemination. Guideline and Conflicts of Interest All members of the Expert Panel complied with the ASCO and AUA policies on conflicts of interest, which require disclosure of any financial or other interest that might be construed as constituting an actual, potential, or apparent conflict. Members of the Expert Panel completed disclo- sure forms and were asked to identify ties to companies developing products that promulgation of the guideline might affect. Information was requested regarding em- ployment, consultancies, stock ownership, honoraria, re- search funding, expert testimony, and membership on company advisory committees. The Panel made decisions on a case-by-case basis as to whether an individual’s role should be limited as a result of a conflict. No limiting conflict was identified. Revision Dates At biannual intervals, the Panel Co-Chairs and two Panel members designated by the Co-Chairs will examine cur- rent literature to determine if there is a need for revisions to the guideline. If necessary, the entire Panel will recon- vene to discuss potential changes. When appropriate, the Panel will recommend revision of the guideline to the ASCO HSC, the ASCO Board, the AUA Practice Guide- lines Committee, and the AUA Board for review and ap- proval. Definition of Terms Period prevalence: the proportion of the randomized pop- ulation identified as having prostate cancer over the trial period. 5-␣-reductase: an enzyme that converts testosterone into the more potent dihydrotestosterone (DHT). 5-␣-Re- ductase has two isoenzymes (isoforms): types 1 and 2. Finasteride inhibits the type 2 isoenzyme, whereas dutas- teride inhibits both the type 1 and type 2 isoenzymes. Primary prevention: Intervention for relatively healthy individuals with no invasive cancer and an average risk for developing cancer.15 Chemoprevention: the use of chemical compounds to reduce the risk of development of a specific disease (as used here, specifically for the reduction in risk of develop- ing prostate cancer). LUTS: Lower urinary tract [obstructive] symptoms. AUA Symptom Index/International Prostate Symptom Score (IPSS): a symptom index for BPH, developed by the AUA. The IPSS consists of seven questions, with scores ranging from 0 to 35. A score between 0 and 7 is consid- ered to represent mild symptoms; 8 to 19, moderate; and 20 to 35, severe. A change in score by 2 to 3 points is generally accepted as clinically meaningful (ie, morbid and/or life threatening). Summary of Outcomes Assessed The primary outcome assessed was either prostate cancer incidence or period prevalence, in prostate cancers de- tected “for cause.” For-cause cancers were defined as those that (1) were suspected clinically during the course of the trial because of symptoms, abnormal digital rectal exam, or abnormal PSA (ie, a PSA that exceeded a certain value or rate of increase over time) and were confirmed on bi- opsy; or (2) during the trial, a recommendation was made for biopsy according to the study protocol (eg, due to in- creasing PSA) which was never done, and end-of-study biopsy showed prostate cancer; or (3) end-of-study biopsy in the setting of a PSA more than 4 or a suspicious digital rectal examination (DRE) showed prostate cancer. Other primary outcomes assessed were distribution of stage of prostate cancer, Gleason scores, and incidence or period prevalence of prostate cancer by age, race, baseline PSA, and family history. Secondary outcomes included prostate cancer detected purely for reasons dictated by study protocol, rather than by clinical indication (eg, an end-of-study biopsy was re- quired per protocol despite a PSA Յ4 ng/mL, and DRE not suggestive of cancer), and overall incidence or period prev- alence of prostate cancer (ie, cancers detected for cause plus cancers detected by study protocol). Other secondary outcomes included quality of life; change in validated uri- nary symptom scale scores (IPSS/AUA); BPH progression (development of acute urinary retention, interventions for treatment of LUTS, medications and herbal therapies to treat LUTS, surgical interventions); overall mortality; prostate cancer-specific mortality; adverse events (impo- tence, retrograde ejaculation, decreased ejaculate volume, decreased libido, gynecomastia); and cost effectiveness. Neither formal cost effectiveness nor decision analysis was planned for the guideline, although the Panel consid- ered available reports. RESULTS Literature Search Wilt et al14 identified 15 RCTs that met the inclu- sion criteria; nine of these trials reported prostate cancer period-prevalence. Previous Guidelines and Consensus Statements Updated in 2003,7 the 1999 AUA guideline on the management of benign prostate hyperplasia can be summarized as follows: Finasteride, a 5-ARI, demonstrates both efficacy and acceptable safety for treatment of LUTS due to BPH. Finasteride can reduce the size of the prostate, can increase peak urinary flow rate, and can reduce BPH symptoms. With finasteride, the average pa- tient experiences a 3-point improvement in the AUA Symptom Index. In general, patients perceive this level of symptom improvement as a meaningful 5␣-REDUCTASE INHIBITORS GUIDELINE 1645
  5. 5. change. Finasteride is ineffective for relief of lower urinary tract obstructive symptoms in patients who do not have enlarged prostates. Reported adverse events are primarily sexually related; they include decreased libido, ejaculatory dysfunction, and erec- tile dysfunction, which are reversible and therefore uncommon after the first year of therapy. Symptom score improvement is not substantially greater among men with very large versus only moderately enlarged prostates; however, because of the more progressive nature of the disease in men with larger glands or higher PSA values, such patients conser- vatively treated (watchful or placebo groups) face an increasingly higher risk of complication, thereby en- hancing the difference over time in outcomes be- tween finasteride and no treatment or placebo groups. In summary, finasteride reduces the risk of sub- sequent acute urinary retention and the need for BPH-related surgery with the absolute benefit in- creasing with rising prostate volume or serum PSA. Finasteride is not appropriate treatment for men with LUTS who do not have any prostatic enlarge- ment. RECOMMENDATIONS Should Men Routinely Be Offered a 5-ARI for the Chemoprevention of Prostate Cancer? Asymptomatic men with a PSA Յ3.0 who are regularly screened with PSA or are anticipating un- dergoing annual PSA screening for early detection of prostate cancer may benefit from a discussion of the benefits of 5-ARIs for 7 years for the prevention of prostate cancer and the potential risks (including the possibility of high-grade prostate cancer) to be able to make a better-informed decision. Men who are taking 5-ARIs for benign conditions such as LUTS would benefit from a similar discussion. Of note, one Panel member believed that the ex- planation of decreased prostate cancer period prev- alence in the finasteride arm of the PCPT is attrib- utable to differential biopsy rates between the two trial arms. The 25% risk reduction is based primar- ily on the PCPT and the risk reduction of a prostate diagnosis accrued primarily as a result of the lower rates of biopsy among men on finasteride. For those men who underwent a biopsy, the risk reduction was a statistically nonsignificant 10%. By contrast, the principal investigator of the PCPT has published a commentary stating that differential biopsy rate is not likely to account for a substantial proportion of the observed difference. He argues that critics of the PCPT “. . . ignore the effects of PSA, DRE, and bi- opsy detecting the cancer in the finasteride group, which would be expected to further reduce the risk of cancer overall.” Evidence Summary The summary of evidence of the effect of 5-ARIs on prostate cancer period prevalence is based on nine RCTs in which administration of the 5-ARI ranged from 1 to 7 years.14 Two additional trials lasting at least 6 months provided data on BPH-related out- comes and adverse effects. Most of the trials were placebo controlled and double-blinded (Appendix Table A2). The results of all trials were generally consistent. The most salient end point chosen by the Panel was the comparison in trials of at least 1 year duration of period prevalence of for-cause prostate cancers between study arms, as defined in the Meth- ods section and glossary, using an intent-to-treat analysis (five studies). This end point comes closest to addressing prevention of those cancers that are considered most important in clinical decision mak- ing—those diagnosed because of symptoms, DRE that is clinically suggestive, or a PSA that triggers a biopsy. Only one of the randomized trials, the pla- cebo-controlled PCPT, was specifically designed to assess the period prevalence of prostate cancer in generally healthy men without underlying moderate or severe lower urinary track symptoms. The PCPT was the largest trial in the literature, with 18,882 of the total 33,403 participants in trials receiving at least 1 year of active therapy. The PCPT also con- tributed approximately 85% (1,006 of 1,188) of the for-cause cancers in the systematic review.14 Men in all of the trials were screened regularly for prostate cancer with PSA and DRE. Therefore, the literature reviewed does not allow assessment of the impact of 5-ARIs on the period prevalence of prostate cancer among men who are not being actively screened for prostate cancer. Review of Relevant Literature What is the impact of 5-ARIs on the risk of incident prostate cancer, prostate cancer mortality, and over- all mortality? Do benefits and harms of 5-ARIs vary among identifiable subpopulations (eg, age, race/eth- nicity, family history, baseline risk for prostate can- cer) and by type of 5-ARI? 5-ARIs decrease the period prevalence of for- cause prostate cancer by approximately 26% (rela- tive risk ϭ 0.74; 95% CI, 0.67 to 0.83; Fig 1). The absolute risk reduction is about 1.4% (4.9% in con- trols v 3.5% in 5-ARI arms), although this may vary with the age of the treated population. (For compar- ison, the data from the Breast Cancer Prevention Trial3 suggest that about 100 women with a 2% baseline risk of breast cancer would have to be treated for approximately 6 years with tamoxifen to prevent one case of invasive breast cancer.) The relative risk of any prostate cancer with 5-ARI treat- 5␣-REDUCTASE INHIBITORS GUIDELINE1646
  6. 6. ment versus controls was 0.74 (95% CI, 0.56 to 0.98), for an absolute risk reduction of 2.9% (9.2% v 6.3%; Fig 2). The PCPT is the most relevant of the trials con- sidered because its target population was men with at most mild lower urinary track symptoms who had a normal DRE and PSA less than 3 ng/mL at study entry. This population is probably closest to a true primary prevention population. In the PCPT, the relative risk of for-cause prostate cancers among those receiving finasteride versus placebo was 0.76 (95% CI, 0.68 to 0.86). This reduction corresponds to the need to treat approximately 71 healthy men for approximately 7 years to prevent one case of pros- tate cancer (95% CI, 50 to 100). Only the PCPT reported subgroup results by race/ ethnicity, age, and family history of prostate cancer. The data showed no apparent difference in efficacy of finasteride within any of these subgroups (Appen- dix Table A3), but estimates are necessarily impre- cise, especially with regard to race/ethnicity, be- cause approximately 92% of the participants in the PCPT were non-Hispanic whites. Importantly, the participants in all the trials were being actively screened for prostate cancer. This study design issue affects the interpretation of the potential effect of 5-ARIs on the risk of develop- ing prostate cancer. For example, regular screening with PSA is known to double the incidence of diag- nosed prostate cancer.16 The relative reduction in risk of being diagnosed with prostate cancer of ap- proximately 26% must be interpreted in this con- text, yielding a net increase in prostate cancer diag- noses of approximately 48% for the combined strategy of screening plus chemoprevention. The studies provide no information as to whether the magnitude of risk reduction for the diagnosis of prostate cancer achieved by 5-ARIs would be the same, or considerably less, in men who are not being actively screened for prostate cancer. Study Review: 5-alpha reductase inhibitors (5-ARIs) and prostate cancer prevention Comparison: 5-ARI versus placebo Outcome: Prostate cancer detected “for cause” 5-ARI Placebo IC%59N/nN/nyrogetacbusro 01 Finasteride: Mid-term duration (1 to 2 years) FSG American 1992 3/595 1/300 1.51 (0.16 to 14.48) FSG Int. 1993 5/495 3/255 0.86 (0.21 to 3.56) PROSPECT 1996 )49.1ot21.0(94.0303/6013/3 Subtotal (95% CI) 1,400 858 0.74 (0.30 to 1.79) Total events: 11 (5-ARI), 10 (Placebo) Test for heterogeneity: χ2 = 0.78, df = 2, P = .68, I2 = 0% Test for overall effect: z = 0.67, P = .50 02 Finasteride: Long-term treatment duration (> 2 years) PCPT 2003 435/9,423 571/9,459 0.76 (0.68 to 0.86) PLESS 1998 36/1,524 45/1,516 0.80 (0.52 to 1.23) Subtotal (95% CI) 10,947 10,975 0.77 (0.68 to 0.86) Total events: 471 (5-ARI), 616 (Placebo) Test for heterogeneity: χ2 = 0.03, df = 1, P = .86, I2 = 0% Test for overall effect: z = 4.45, P < .00001 03 Dutasteride: Long-term treatment duration (> 2 years) ARIA/ARIB 2004 27/2,167 55/2,158 0.49 (0.31 to 0.77) Subtotal (95% CI) 2,167 2,158 0.49 (0.31 to 0.77) Total events: 27 (5-ARI), 55 (Placebo) Test for heterogeneity: not applicable Test for overall effect: z = 3.07, P = .002 Total (95% CI) 14,514 13,991 0.74 (0.67 to 0.83) Total events: 509 (5-ARI), 681 (Placebo) Test for heterogeneity: χ2 = 4.31, df = 5, P = .51, I2 = 0% Test for overall effect: z = 5.17, P < .00001 0.2 0.5 1 2 5 Favors 5-ARI Favors Placebo 95% CI RR (fixed) RR (fixed) Figure 1. Prostate cancer detected for cause. 5-ARI, 5-␣-reductase inhibitor; RR, relative risk; FSG, Finasteride Study Group; PROSPECT, Proscar Safety Plus Efficacy Canadian Two-Year study; PCPT, Prostate Cancer Prevention Trial; PLESS, Proscar Long-Term Efficacy and Safety Study. Adapted with permission from the Cochrane Collaboration. 5␣-REDUCTASE INHIBITORS GUIDELINE 1647
  7. 7. None of the trials was large enough to detect clinically important differences in either prostate cancer-specific mortality or overall mortality, and no difference was noted. The summary relative risk of prostate cancer-specific mortality from the random- ized trials was 1.00, with wide 95% CIs (0.29 to 3.47). Likewise, the relative risk for all-cause mor- tality for 5-ARIs versus controls was 1.06 (95% CI, 0.95 to 1.18). Absolute rates of prostate cancer mor- tality and overall mortality were 0.5% and 5.0%, respectively. Nevertheless, the Panel judged that even if 5-ARI treatment never translates into re- duced overall or prostate cancer-specific mortality, reduction in risk of prostate cancer diagnosis with the consequent morbidity of treatment is a clinically beneficial end point in and of itself. Do 5-ARIs have a differential effect on the devel- opment of different histologic grades or stages of prostate cancer? Are any such differences likely to modify the curability of prostate cancer when diag- nosed? Is the Gleason histologic grading system for prostate cancer applicable to men who are receiving 5-ARIs or other interventions that target the andro- gen pathway? The original publication and analysis of the PCPT screening trial5 reported a statistically significant reduction in the 7-year period prevalence of prostate cancer when finasteride was compared with placebo. A secondary analysis showed an unexpected statis- tically significant greater number of high Gleason grade cancers in the finasteride treatment arm. For every thousand men, finasteride reduced the num- ber of prostate cancers from 60 to 45; however, if the observations represent a true finding, the number of high-grade cancers would increase from 18 to 21 in this cohort.14 The concern of paramount importance was the potential causal relationship of finasteride to high-grade cancer. The PCPT investigators, prac- 01 Finasteride: Mid-term treatment duration (1 to 2 years) Cote 1998 8/27 1/25 7.41 (1.00 to 55.09) FSG American 1992 3/595 1/300 1.51 (0.16 to 14.48) FSG Int. 1993 )65.3ot12.0(68.0552/3594/5 PROSPECT 1996 3/310 6/303 0.49 (0.12 to 1.94) Subtotal (95% CI) 1,427 883 1.23 (0.40 to 3.78) Total events: 19 (5-ARI), 11 (Placebo) Test for overall effect: z = 0.37, P = .71 02 Finasteride: Long-term treatment duration (> 2 years) PCPT 2003 803/9,423 1,147/9,459 0.70 (0.65 to 0.77) PLESS 1998 72/1,524 77/1,516 0.93 (0.68 to 1.27) Subtotal (95% CI) 10,947 10,975 0.78 (0.60 to 1.01) Total events: 875 (5-ARI), 1,224 (Placebo) Test for heterogeneity: χ2 = 2.86, df = 1, P = .09, I2 = 65.1% Test for overall effect: z = 1.91, P = .057 03 Dutasteride: Long-term treatment duration (> 2 years) ARIA/ARIB 2004 27/2,167 55/2,158 0.49 (0.31 to 0.77) Subtotal (95% CI) 2,167 2,158 0.49 (0.31 to 0.77) Total events: 27 (5-ARI), 55 (Placebo) Test for heterogeneity: not applicable Test for overall effect: z = 3.07, P = .002 Total (95% CI) 14,541 14,016 0.74 (0.56 to 0.98) Total events: 921 (5-ARI), 1,290 (Placebo) Test for heterogeneity: χ2 = 11.51, df = 6, P = .07, I2 = 48.0% Test for overall effect: z = 2.09, P = .036 0.1 0.2 0.5 1 2 5 10 Favors 5-ARI Favors Placebo obecalPIRA-5ydutS IC%59N/nN/nyrogetacbusro Test for heterogeneity: χ2 = 5.17, df = 3, P = .16, I2 = 42.0% 95% CI Review: 5-alpha reductase inhibitors (5-ARIs) and prostate cancer prevention Comparison: 5-ARI versus placebo Outcome: Prostate cancer detected overall RR (random) RR (random) Figure 2. Prostate cancer detected overall. 5-ARI, 5-␣-reductase inhibitor; RR, relative risk; FSG, Finasteride Study Group; PROSPECT, Proscar Safety Plus Efficacy Canadian Two-Year study; PCPT, Prostate Cancer Prevention Trial; PLESS, Proscar Long-Term Efficacy and Safety Study. Adapted with permission from the Cochrane Collaboration. 5␣-REDUCTASE INHIBITORS GUIDELINE1648
  8. 8. ticing physicians, and the Panel all struggled with the question of whether the increase in high-grade cancers reflected a real risk of finasteride or merely confounding factors. Several subsequent analyses of the data from the trial have addressed this question. An initial con- cern centered about the morphologic and histopatho- logic alterations that might be attributed to a hor- monal agent or an agent, such as finasteride, which alters the hormonal milieu. Might morphologic changes caused by finasteride mimic high-grade cancer, and therefore artifactually produce a higher Gleason reading? A detailed pathologic review elim- inated the questions of morphologic artifact as a reason for the higher number of Gleason grade tu- mors in the finasteride arm.17 A second question that was addressed by the PCPT investigators was the degree of sampling er- ror induced by the established effect of 5-ARIs on reduction in prostate volume. Finasteride reduces prostate volume by approximately 25% to 30%.5,9,10,18 The smaller the prostate volume, the less likely the sampling error using the PCPT’s pro- tocol-prescribed systematic sextant needle biopsies. Biopsies of the smaller prostates increase the likeli- hood of detection of prostate cancer of all grades. If finasteride is more effective in preventing low-grade tumors than high-grade tumors, it is possible to observe a reduction in overall period prevalence of cancers, a reduction in low- and moderate-grade cancers, but an absolute increase in high-grade can- cers as a consequence of less sampling error in the finasteride arm. Indeed, modeling incorporating prostate volume suggests that the increase in high- grade cancers seen in the PCPT may be nearly com- pletely explained by enhanced detection and not tu- mor transformation or induction, and would not be expected to translate into an increase in prostate cancer mortality.18 A series of multivariable logistic regression mod- els was used to predict the incidence of high-grade cancer in the finasteride and placebo arms.19 A model that did not incorporate grading information from radical prostatectomies showed a nonsignifi- cant 14% increase in high-grade cancer (P ϭ.12) in the finasteride group; however, incorporating infor- mation on grading led to a 27% lower (P ϭ .02) bias-adjusted estimated rate of high-grade cancer in the finasteride arm (6.0%) than in the placebo arm (8.2%). Although subject to the uncertainty of mod- eling assumptions outcomes, this analysis lends ad- ditional support against high-grade disease induc- tion by finasteride. A third question of potential bias revolves around the possibility of differences between the finasteride and placebo study arms of the PCPT in the operating characteristics of PSA and DRE. Analysis by re- ceiver operating characteristic curves demonstrate heightened sensitivity of both PSA and DRE in the finasteride arm relative to the placebo arm, suggest- ing an enhanced suspicion for (and detection of) prostate cancer in the finasteride arm.20 It is reas- suring that despite the greater proportion of pa- tients with biopsy Gleason scores of Ն7 in the finas- teride group relative to placebo, patients from the two groups who subsequently were treated with rad- ical prostatectomy showed no difference in patho- logic stage, nodal involvement, or margin status. This observation, however, was possibly driven by differential choices in the decision to undergo radi- cal prostatectomy. In summary, the Panel judged that plausible rea- sons could have led to a spurious increase in high- grade cancers. The Panel believed that it was un- likely for an agent to increase the incidence of high- grade tumors and simultaneously decrease the incidence of low-grade tumors. Furthermore, at this time there is no known pathologic adjustment factor for men diagnosed with prostate cancer while taking a 5-ARI versus men not taking a 5-ARI. Nor is there information on the long-term outcomes for a given histologic grade for men taking a 5-ARI versus men not having received a 5-ARI. Therefore, until this information is known, decisions regarding the nat- ural history of the disease and decisions regarding treatment interventions should be based on the his- tologic information obtained on biopsy, regardless of 5-ARI status. Such an effect would be difficult to explain on the basis of known biologic mechanisms. Nevertheless, none of the observations provides proof that finasteride would not increase the true incidence of high-grade cancers. Therefore, men should be fully apprised of the remaining uncer- tainty surrounding high-grade cancers with finas- teride. Lastly, a detailed analysis of core biopsy speci- mens compared standard prognostic findings for cancers detected in the finasteride and placebo arms and made the following observations. For cancers assigned Gleason score Յ6, the mean number of cores positive was 1.4 in the finasteride arm and 1.55 in the placebo arm (P ϭ .024); the mean per- centage of cores positive for Gleason score 7 was 31.2 and 36.7 (P ϭ .009); and for cancers assigned Glea- son score Ն8, bilateral core positivity was 28.6% in the finasteride arm and 44.6% in the placebo arm (P ϭ .047). These data suggest that men taking finasteride had smaller, less aggressive tumors ver- sus men taking placebo.21 Apart from chemoprevention for prostate cancer, many men take a 5-ARI for indications such as lower urinary tract obstructive symptoms or male pattern baldness. The observed increase in high-grade pros- tate cancers in men receiving finasteride in the 5␣-REDUCTASE INHIBITORS GUIDELINE 1649
  9. 9. PCPT, and the theoretical possibility of increased risk of prostate cancer mortality, should be dis- cussed with these men. The considerations men- tioned above provide some reassurance that the in- crease in diagnosis of high-grade tumors is more likely to be due to artifact than to an actual increase in aggressive cancers. In such cases, observed bene- fits must be weighed against theoretical harms in men who are being treated for symptomatic or both- ersome conditions. What Is the Impact of 5-ARIs on the Need for Treatment for Benign Prostatic Disease? 5-ARIs are established, US Food and Drug Ad- ministration-approved, treatments for symptomatic BPH. The systematic review of trials in men with established BPH confirmed the efficacy of this class of drugs for this condition. To date, only the PCPT provides information that directly addresses the im- pact of 5-ARIs in relatively asymptomatic men who do not require treatment of urinary tract symptoms. In the PCPT, the incidence of acute urinary reten- tion was decreased by about one third in the finas- teride arm (RR ϭ 0.67; 95% CI, 0.59 to 0.76; absolute rates, 6.3% v 4.2%). Consistent with this observa- tion, the incidence of transurethral resection of the prostate was 1.9% in the placebo arm and 1.0% in the finasteride arm, a statistically significant de- crease in the risk for surgical interventions. What is the impact of 5-ARIs on quality of life? What are other potential harms and adverse effects of 5-ARIs? What are other potential benefits of, and indications for, 5-ARI use (eg, benign prostatic hy- perplasia, male baldness)? Benefits of 5-ARI. The question of the impact of 5-ARIs on global quality of life is difficult to answer based on the available data. Studies of 5-ARIs have not assessed global or general health-related quality of life using traditional quality-of-life measures; rather, most studies have included measures of uri- nary symptoms (eg, urinary retention), sexual func- tioning (eg, erectile dysfunction), and/or endocrine effects (eg, gynecomastia). Mid- and long-term stud- ies (6 months or beyond) with finasteride and dutas- teride individually and in meta-analysis of studies that included men with underlying LUTS demon- strated a reduction in risk in acute urinary retention (from 5.6% to 3.3%; absolute risk difference, 2.3%) as well as a reduction in the need for surgical interven- tion (from 3.3% to 1.7%; absolute risk difference, 1.6%). The largest benefits were observed in men with a baseline PSA greater than 4 ng/mL (larger prostates). In addition, one RCT showed a statisti- cally significant reduction in hematuria with finas- teride compared with placebo.22 Adverse events. 5-ARIs are associated with a con- sistently higher frequency of adverse events than placebo, albeit of small absolute magnitude (Table 1). Virtually all RCTs show a 2% to 4% increase in reported erectile dysfunction and gynecomastia, and decreases in ejaculate volume and libido for the treatment arm. When all studies, mid- and long- term, were combined, the overall discontinuation or loss to follow-up rates for both the 5-ARI and placebo arms were approximately 15%. The combined dis- continuation and loss to follow-up rate specifically secondary to adverse events was approximately 6% to 7% in studies in both the 5-ARI and placebo patients. When the PCPT specifically evaluated ad- verse events, there were more adverse effects caus- ing temporary discontinuation in the finasteride arm (the investigators do not specifically define tempo- rary in this setting). Sexual function and endocrine effects, which were more common in the 5-ARI arm (statistically significant), included decreased libido, decreased ejaculate volume, and gynecomastia. The sexual dysfunction associated with finasteride de- creased over time, although it remained statistically significant. The magnitude of effect was smaller than natural sources of variability in the study pop- ulation23 ; on a scale of 0 to 100 (a higher score indicates more sexual dysfunction), the largest effect of finasteride on sexual functioning was a difference (mean) of 3.21 points, compared with a difference of 1.26 points for each year of older age. In trials comparing 5-ARIs to an alpha blocker for the management of LUTS, discontinuation rates were similar in the two groups. Dizziness and pos- tural hypertension were statistically more frequent among patients receiving 5-␣ blocker therapy.10,24,25 5-ARIs effect on PSA. The decrease in PSA levels by 5-ARIs must be taken into account when judging the significance of a PSA level. In the PCPT, finasteride lowered the PSA by 50% after 12 months of therapy, and therefore a multiplier of 2 was used as a crite- rion for biopsy. The effects of 5-ARIs on PSA before 12 months are variable. In the PCPT, the decline at 3 years was greater than 50% which was adjusted by changing the 2 multiplier in the finasteride arm to 2.3. A single study has investigated the changes in PSA level caused by a 1-mg dose, as is used in treatment of male pattern baldness.26 For men age 50 years and older, 1 mg of finasteride had an effect similar to 5 mg (50% decrease) at the 1-year fol- low-up date. Information beyond 1 year is not available. Dutasteride inhibits both the type 1 and type 2 isoforms of 5-␣ reductase and causes a greater and more consistent decrease in DHT. The amount of PSA suppression with long-term dutasteride treat- ment has not been reported. 5␣-REDUCTASE INHIBITORS GUIDELINE1650
  10. 10. In conclusion, a consistently uniform scale multi- plier is currently unavailable because of inter- and intraindividual variability of PSA levels, laboratory variables, variable compliance of patients with re- gard to drug schedule, and a paucity of data relating change of PSA to duration of therapy. No specific cut point or change in PSA has been prospectively vali- dated in men taking a 5-ARI. What is the treatment duration required for best outcome (period versus lifelong)? No trial has directly compared different durations of 5-ARIs for the prevention of prostate cancer. The PCPT was the only reported trial designed to test the efficacy of a 5-ARI (finasteride) for preventing prostate cancer. It is also the most reliable trial for directly comparing the benefits and harms of finasteride in the most likely target population for interventions to prevent prostate cancer. Given that finasteride was administered for a planned 7 years, the Panel judged that until additional in- formation is available, finasteride should be given for 7 years if used for primary prevention. One ongoing trial13 compares dutasteride with placebo for preventing prostate cancer. Dutasteride is ad- ministered for 4 years in that trial, so the results of the trial should help address the question of Table 1. Adverse effects Subgroup/Reference 5-␣-Reductase Inhibitor Placebo Relative Risk 95% CINo./Total No. % No./Total No. % Impotence/erectile dysfunction Mid-term treatment duration (1 to 2 years) ARIA/ARIB8 13/1,605 0.81 14/1,555 0.90 0.90 0.42 to 1.91 FSG-American47 25/595 4.2 5/300 1.7 2.52 0.97 to 6.52 FSG-International48 22/495 4.4 1/255 0.4 11.33 1.54 to 83.60 PREDICT24 13/264 4.9 9/269 3.3 1.47 0.64 to 3.38 PROSPECT41 49/310 15.8 19/303 6.2 2.52 1.52 to 4.18 VA COOP25 29/310 9.4 14/305 4.6 2.04 1.10 to 3.78 Long-term treatment duration (Ͼ2 years) PCPT5 6,349/9,423 67.4 5,816/9,457 61.5 1.10 1.07 to 1.12 Total 6,500/13,002 50.0 5,878/12,444 47.2 1.71 1.11 to 2.65 Decreased/abnormal ejaculate volume Mid-term treatment duration (1 to 2 years) FSG-American47 26/595 4.4 5/300 1.7 2.62 1.02 to 6.76 VA COOP25 6/310 1.9 4/305 1.3 1.48 0.42 to 5.18 Long-term treatment duration (Ͼ2 years) PCPT5 5,690/9,423 60.4 4,473/9,457 47.3 1.28 1.24 to 1.31 Finasteride Long-Term Efficacy and Safety Study Group36 23/1,524 1.5 8/1,516 0.53 2.86 1.28 to 6.37 Total 5,745/11,852 48.5 4,490/11,578 38.8 1.75 1.07 to 2.85 Decreased libido Mid-term treatment duration (1 to 2 years) ARIA/ARIB8 91/2,167 4.2 46/2,158 2.1 1.97 1.39 to 2.79 FSG-American47 32/595 5.4 4/300 1.3 4.03 1.44 to 11.30 PREDICT24 9/264 3.4 5/269 1.9 1.83 0.62 to 5.40 PROSPECT41 31/310 10.0 19/303 6.2 1.59 0.92 to 2.76 VA COOP25 14/310 4.5 4/305 1.3 3.44 1.15 to 10.34 Long-term treatment duration (Ͼ2 years) PCPT5 6,163/9,423 65.4 5,635/9,457 59.6 1.10 1.07 to 1.22 Total 6,340/13,069 48.5 5,713/12,792 44.7 1.83 1.19 to 2.81 Gynecomastia Mid-term treatment duration (1 to 2 years) ARIA/ARIB8 50/2167 2.3 16/2158 0.74 3.11 1.78 to 5.45 Long-term treatment duration (Ͼ2 years) PCPT5 426/9,423 4.5 261/9,457 2.8 1.64 1.41 to 1.91 Total 476/11,590 4.1 277/11,615 2.4 2.13 1.15 to 3.95 Incontinence Long-term treatment duration (Ͼ2 years) MTOPS10 7/768 0.91 6/737 0.81 1.12 0.38 to 3.32 PCPT5 183/9,423 1.9 208/9,457 2.2 0.88 0.73 to 1.07 Total 190/10,191 1.9 214/10,194 2.1 0.89 0.73 to 1.08 Increased urinary frequency/urgency PCPT5 1,214/9,423 12.9 1,474/9,457 15.6 0.83 0.77 to 0.89 Abbreviations: FSG, Finasteride Study Group; PREDICT, Prospective European Doxazosin and Combination Therapy trial; PROSPECT, Proscar Safety Plus Efficacy Canadian Two-Year study; VA COOP, Veterans Affairs Cooperative Studies BPH Study Group; PCPT, Prostate Cancer Prevention Trial. MTOPS, Medical Therapy of Prostatic Symptoms. Adapted with permission from the Cochrane Collaboration. 5␣-REDUCTASE INHIBITORS GUIDELINE 1651
  11. 11. whether a shorter duration of a 5-ARI prevents prostate cancer. What are the future directions of research regard- ing 5-ARIs for the prevention of prostate cancer? The goal of developing a chemopreventive agent that can reduce the risk of prostate cancer has been achieved. Nevertheless, despite the availability of one large and well-designed trial (PCPT) and an ongoing large trial (REDUCE) to test the efficacy of finasteride and dutasteride, respectively, for the pri- mary prevention of prostate cancer, important ques- tions and directions for research remain. The critical question regarding the effect of 5-ARIs on prostate cancer morbidity and mortality is yet to be an- swered: is the observed increase in higher grade prostate cancers in men receiving finasteride in the PCPT real or artifactual? Additional investigation is necessary, and the results of REDUCE will aid in this assessment. The dose of finasteride currently being used to treat male pattern baldness is 1 mg per day rather than the 5 mg per day used in the PCPT. It is unknown if a 1-mg dose is as effective as 5 mg in reducing the risk of prostate cancer. If the lower dose is just as effective, the balance of benefits and harms would be more favorable. All of this informa- tion would be critical to making more reliable esti- mates of cost effectiveness of 5-ARIs for preventing prostate cancer. It would also be important to know whether 5-ARIs reduce the incidence of clinically detected cancer among men who are not being ac- tively screened. This would be especially pertinent should the ongoing randomized trials of prostate cancer screening (Prostate, Lung, Colorectal, Ovary [PLCO] Screening Study; European Randomized Study of Prostate Cancer [ERSPC]) show that pros- tate cancer screening does not decrease prostate cancer mortality or that the harms of screening out- weigh the benefits. In addition, as mentioned above, men taking a 5-ARI are expected to experience a roughly 50% reduction in PSA by 12 months; how- ever, because these changes in PSA may vary across men, and within individual men over time, the Panel cannot recommend a specific cut point to trig- ger a biopsy for men taking a 5-ARI. This is an important topic for future research. Behavioral and communication research is needed on the type and effectiveness of information for men considering the use of a 5-ARI for preven- tion of prostate cancer and for men who are already taking a 5-ARI for other indications. More generally, as models incorporating molecular data evolve, risk- stratification models may be developed to tailor in- dividual preventive therapy. Such models may in- clude individuals with germline susceptibility at heightened risk for developing prostate cancer, es- pecially earlier onset disease or as a second malignancy. PHYSICIAN-PATIENT COMMUNICATION Although the decision to embark on a preventive 5-ARI regimen belongs in the final analysis to the individual, the physician has an important role. For the man who is considering the use of these agents for prostate cancer prevention, it is essential that the physician present the available data and high- light the remaining uncertainty. 5-ARIs do not eliminate the risk of developing prostate cancer; they reduce its clinical incidence. This distinction should be made clear. The advisabil- ity of the drug as a chemopreventive agent depends on an estimate of probabilities—of risk. As yet, there is no widely established decision model or aid that can help a man of age 50 or 60 years determine if he is well advised to take a 5-ARI. Thompson et al27,28 have developed a prostate cancer risk calcu- lator based on risk equations generated from the PCPT data that may have clinical applications. The risk calculator is applicable to men who are similar to those who participated in the PCPT: at least 50 years of age, no prior prostate cancer diagnosis, and PSA and DRE results that are less than 1 year old. The calculator provides a preliminary assessment of prostate cancer risk and the risk of high-grade pros- tate cancer if a prostate biopsy is performed, and was recently validated in a more ethnically diverse and a younger population than that studied in the PCPT.29 The calculator is accessible at http://www. compass.fhcrc.org/edmnci/bin/calculator/main.asp? tϭprostate&subϭdisclaimer&vϭprostate&mϭ&xϭ Prostate%20Cancer. It is uncertain whether the findings of increased high-grade cancers on the finasteride arm of the PCPT are actually an artifact of the methodology of the PCPT itself, as many believe. Until that risk is better elucidated, physicians should be explicit about the uncertainties. In addition, it is important to point out that the impact of 5-ARIs on prostate cancer mortality is unknown, given that the PCPT was not designed to address this question. Never- theless, it is clear that a 5-ARI does convey benefits to some men, as it decreases the overall incidence of prostate cancer and also prevents urinary tract ob- struction in some men. In communicating the present state of knowledge about the risks and benefits of 5-ARIs, it may be helpful to use the model of a cohort of 1,000 men taking 5-ARIs for 7 years. Based on the systematic review by Wilt et al,14 it is estimated that 5-ARIs will result in a reduction of 15 prostate cancer cases in this group of 1,000 men, and in a possible increase 5␣-REDUCTASE INHIBITORS GUIDELINE1652
  12. 12. of three cases of high-grade cancer after approxi- mately 7 years of therapy. Men also should be informed that no information on the long-term effects of 5-ARIs exists beyond approximately 7 years, and that whether or not the reduction in prostate cancer incidence will translate into a reduction in prostate cancer mortality or longer life expectancy remains unknown. Physicians should inform men who are consider- ing a 5-ARI about the incidence of sexual adverse effects. Such adverse effects as lowered libido asso- ciated with a 5-ARI have been reported consistently, but they are also reversible. The benefits of a 5-ARI in reducing BPH are also appreciable and unequiv- ocal. It has been suggested that the ideal candidate for a 5-ARI regimen would be an individual who is “concerned about the development of prostate can- cer, has a higher-than-average risk of the disease, has urinary symptoms that may be relieved by fin- asteride, and is not sexually active.”30 In summary, it is recommended that the physi- cian: 1. inform the man who is considering a 5-ARI that these agents reduce the incidence of prostate can- cer, and be sure to be clear that these agents do not reduce the risk of prostate cancer to zero; 2. discuss the elevated rate of high-grade cancer observed in the PCPT and inform men of the potential explanations; 3. make it known to men that no information on the long-term effects of 5-ARIs on prostate cancer incidence exists beyond approximately 7 years, and that whether or not a 5-ARI reduces prostate cancer mortality or increases life expectancy re- mains unknown; 4. inform men of possible but reversible sexual ad- verse effects; and 5. inform men of the likely improvement in lower urinary tract symptoms. LIMITATIONS OF THE LITERATURE Despite high-quality evidence from randomized trials, the data have limitations. Only one trial reported to date (PCPT) was specifically designed to measure the effect of a 5-ARI on the incidence of prostate cancer; it was not designed with sufficient power to assess the effect of 5-ARIs on the risk of prostate cancer death. To develop a complete assessment of the benefit of 5-ARIs, one would need to know the proportion of cancers finasteride prevents that are truly clinically meaningful. The current literature cannot provide an estimate of this proportion; in particular, data are lacking on clinically meaningful cancers in the age group under consideration (men older than 50 years). A recent analysis of PCPT characterized 34% of can- cers as clinically insignificant by histologic criteria, a rate similar to contemporary series of men who un- dergo treatment.21 Many cancers prevented by finas- teride might never have caused harm, as suggested by the fact that screening leads to substantial overdiag- nosis of nonlethal cancers. Overdiagnosis can increase substantially with a lowering of the PSA threshold for prostatic biopsy or an increase in the number of sys- tematic biopsies of the prostate. Overdiagnosis is likely to decrease if ongoing randomized prostate can- cer screening trials show a net harm from screening. Therefore, the clinical importance of the prostate can- cers diagnosed in existing and ongoing chemopreven- tion trials is difficult to interpret. The Panel attempted to focus on cancers that were most likely to be of clinical importance (for-cause cancers as described in Methods). One of the most serious limitations in the current literature is the changes that occur in stan- dards for PSA thresholds, criteria for biopsy, and bi- opsy methods. Continuing changes may alter all eval- uations of outcomes. Although not specifically within the scope of this document, the Panel did review studies on cost effec- tiveness. Two analyses31,32 have been published on the cost effectiveness of finasteride for prostate cancer pre- vention using the period prevalence observed in the PCPT and making a variety of unverifiable assump- tions about the impact of the diagnosed cancers on prostate cancer mortality and the tumor grade-specific lethality of the cancers detected. The results of the cost-effectiveness analyses were highly dependent on assumptions regarding whether the observed increase in high-grade tumors was real or artifactual, and on the cost of drug. As extensively discussed above, the first assumption cannot be tested. Therefore, the Panel concluded that any assessment of cost effective- ness at this point is unreliable and impossible to in- corporate into the decision of whether or not to take 5-ARIs for lowering the risk of prostate cancer. SUMMARY OF DESIRED OUTCOMES AND INTERPRETIVE SUMMARY For the man who wishes periodic monitoring (oppor- tunistic or organized screening), 5-ARI therapy dur- ing a 7-year period reduces the period prevalence of for-cause cancer diagnoses by approximately 25% (relative risk reduction) for an absolute risk reduc- tion of about 1.4%. Although the majority of the Panel judged that the observed higher incidence of high-grade (Gleason score 8 to 10) cancer in the finasteride group is likely due to confounding fac- tors, the increased incidence of high-grade cancer as a result of induction by the drug cannot be excluded with certainty. Additional benefits accruing from the drug are reduction of the risk of urinary retention and 5␣-REDUCTASE INHIBITORS GUIDELINE 1653
  13. 13. need for surgical intervention. Harms include sexual adverse effects, which usually diminish with time. AUTHOR CONTRIBUTIONS Conception and design: Barnett S. Kramer, Timothy J. Wilt, Robin Zon, Paul Schellhammer Administrative support: Karen L. Hagerty, Mark R. Somerfield Collection and assembly of data: Barnett S. Kramer, Karen L. Hagerty, Mark R. Somerfield, Timothy J. Wilt, Paul Schellhammer Data analysis and interpretation: Barnett S. Kramer, Karen L. Hagerty, Stewart Justman, Peter C. Albertsen, H. Ballentine Carter, Joseph P. Costantino, Jonathan I. Epstein, Paul A. Godley, Timothy J. Wilt, Janet Wittes, Paul Schellhammer Manuscript writing: Barnett S. Kramer, Karen L. Hagerty, Stewart Justman, Mark R. Somerfield, Pe- ter C. Albertsen, Joseph P. Costantino, Jonathan I. Epstein, Timothy J. Wilt, Janet Wittes, Robin Zon, Paul Schellhammer Final approval of manuscript: Barnett S. Kramer, Stewart Justman, Peter C. Albertsen, William J. Blot, H. Ballentine Carter, Joseph P. Costantino, Jonathan I. Epstein, Paul A. Godley, Russell P. Har- ris, Timothy J. Wilt, Janet Wittes, Robin Zon, Paul Schellhammer ACKNOWLEDGMENTS The Expert Panel thanks Erik Busby, MD, William Dahut, MD, Bernard Levin, MD, Ethan Basch, MD, J. Leonard Lichtenfeld, MD, Dean F. Bajorin, MD, Bruce J. Roth, MD, the ASCO Health Services Com- mittee and Board of Directors and the AUA Practice Guidelines Committee, Board of Directors and staff, Edie Budd, and Heddy Hubbard, PhD. TABLE A1 5-␣-Reductase Inhibitors Panel Members Panel Member Institution Barnett Kramer, MD, Co-Chair National Institutes of Health Paul Schellhammer, MD, Co-Chair Eastern Virginia Medical School Stewart Justman, PhD, Patient Representative University of Montana Liberal Studies Peter C. Albertsen, MD University of Connecticut Health Center William J. Blot, PhD International Epidemiology Institute, Vanderbilt-Ingram Cancer Center H. Ballentine Carter, MD Johns Hopkins University Joseph P. Costantino, PhD National Surgical Adjuvant Breast and Bowel Project Jonathan I. Epstein, MD Johns Hopkins University Paul A.Godley, MD, PhD University of North Carolina at Chapel Hill Russell P. Harris, MD, MPH University of North Carolina at Chapel Hill Timothy J. Wilt, MD, MPH Minneapolis VA Center for Chronic Disease Outcomes Research Janet Wittes, PhD Statistics Collaborative Robin Zon, MD Michiana Hematology Oncology TABLE A2 Characteristics for 5-ARI Studies Study (references) and Interventions (dose/d) No. of Randomly Assigned Patients Treatment Duration (years) Baseline Demographic Characteristics Long-term trials (Ͼ2 years) PCPT5 7 (Ϯ 90 days) American men enrolled onto a prostate cancer prevention trial Finasteride, 5 mg 9,423 Age, 45–64 years, 62%; Ն65 years, 38% Placebo 9,459 Race/ethnicity: white, 92%; black, 3.8%; Hispanic, 2.6%; other, 1.5% PSA (ng/mL), Յ3: 100% Family history of PCa (first-degree relative): 15.4% Mean baseline AUA/IPSS score: 6.7 (SD, 4.8) MTOPS10,33 4.5 American men, mean age 62.6 (SD, 7.3), with LUTS secondary to BPH Finasteride, 5 mg 768 Race/ethnicity: white, 82.3%; black, 8.9%; Hispanic, 7.3%; other, 1.5% Doxazosin, 4–8 mg 756 Mean PSA (ng/mL): 2.4 (SD, 2.1) Combination finasteride and doxazsoin 786 Mean prostate volume (mL): 36.3 (SD, 20.1) Placebo 737 Mean baseline AUA/IPSS score: 16.9 (SD, 5.9) PLESS9,34–37 4.0 American men, mean age 64 years (SD, 6.4), with LUTS secondary BPH Finasteride, 5 mg 1,524 Race: white 95.5% Placebo 1,516 Mean PSA (ng/mL): 2.8 (SD, 2.1). Mean baseline AUA/IPSS score: 15 (SD, 5.7). History of sexual dysfunction: 46% of men in each group at screening (appendix continued) 5␣-REDUCTASE INHIBITORS GUIDELINE1654
  14. 14. TABLE A2 (continued) Study (references) and Interventions (dose/d) No. of Randomly Assigned Patients Treatment Duration (years) Baseline Demographic Characteristics Moderate-term trials (1–2 years) ARIA/ARIB 3001, 3002, 30038,38–40 2.0 Multinational men, mean age 66.3 years, with LUTS secondary BPH (all participants had IPSS Ն12) Dutasteride, 0.5 mg 2,167 Race/ethnicity: white, 92%; black, 4%; Hispanic, 7.3%; Asian, 1%; other, 1.5% Placebo 2,158 Mean PSA (ng/mL): 4.0 (SD, 2.1) Mean prostate volume (cm3 ): 54.5 Mean baseline AUA/IPSS score: 17.05 PROSPECT41 2.0 Canadian men in good health, mean age, 63.3 years (range, 46 to 80 years) with LUTS secondary to BPH Finasteride, 5 mg 310 Race: NR Placebo 303 Mean PSA (ng/mL): NR Mean baseline AUA/IPSS score: 16.2 PREDICT24 1.0 European men, mean age, 64 years (range, 50 to 80 years), with LUTS secondary to BPH (all participants had IPSS Ն12) Finasteride, 5 mg 264 Race: NR Doxazosin, 4–8 mg 275 Mean PSA (ng/mL): 2.6 Combination finasteride and doxazsoin 286 Mean prostate volume (g): 36 Placebo 270 Mean baseline AUA/IPSS score: 17.2 VA Coop (Johnson, 2003; a subset of subjects from Lepor 1996)25,42 1.0 American men, mean age 65 years, with symptomatic BPH Finasteride, 5 mg 252 Race: white 80% Terazosin, 10 mg 262 Race/ethnicity (from Lepor): white, 87%; black, 11%; Asian, 1%; Native American, 0.5% Combination finasteride and terazosin 272 Mean PSA (from Lepor; ng/mL): 2.3 Placebo 254 Mean prostate volume (g): 37.6 Mean baseline AUA/IPSS score: 16.1 Foley, 200022 1.0 British men, mean age, 77.5 years (range, 55 to 89 years), with hematuria associated with BPH Finasteride, 5 mg 29 Race: NR Watchful waiting 28 Mean PSA (ng/mL): NR Mean baseline AUA/IPSS score: NR Cote, 199843 1.0 American men age Ն50 years (mean, 68 years) with elevated PSA (Ͼ4.0 ng/mL); study objective was to examine effect of finasteride on prostate cellular proliferation and high-grade PIN Observation (watchful waiting) 29 Race: NR Finasteride, 5 mg 29 Mean PSA (ng/mL): 9.8 Mean baseline AUA/IPSS score: NR Pre-existing high-grade PIN: observation, 5 men; Finasteride, 8 men FSG44–48 American and international men; mean age, 64.9 years (range, 40 to 83 years) with BPH Finasteride, 1 mg 547 Race/ethnicity: white, 95.8%; black, 1.6%; other, 2.6%. Finasteride, 5 mg 543 Mean PSA (ng/mL): 4.7 Placebo 555 Mean prostate volume (cm3 ): 55.0 Mean baseline AUA/IPSS score: NR Short-term trials (1 year) ARIA 200149 0.5 American and Canadian men age Ն50 years (mean, 62.6 to 65.5 years across groups), with LUTS secondary to BPH; study objective was to examine effect of dutasteride on serum dihydrotestosterone levels Dutasteride, 0.01, 0.05, 0.5, 2.5, and 5 mg 285 Race: NR Finasteride, 5 mg 55 Mean PSA (ng/mL): NR Placebo 59 Mean baseline AUA/IPSS score: NR MICTUS50 0.5 Italian men, mean age, 63 years (SD, 7.1 years), with LUTS secondary to BPH (all participants had IPSS Ն13) Finasteride, 5 mg 204 Race: NR Tamsulosin, 0.4 mg 199 Mean PSA (ng/mL): NR Mean baseline AUA/IPSS score: NR Lee, 200251 Korean men, mean age, 64.7 years, with LUTS secondary to BPH (all participants had Korean IPSS Ͼ8) Finasteride, 5 mg 102 Race: Asian, 100% Tamsulosin, 0.2 mg 103 Mean PSA (ng/mL): 2.0 Mean prostate volume (cm3 ): 29.8 Mean baseline AUA/IPSS score: 19.5 Abbreviations: 5-ARI, 5-␣-reductase inhibitor; PCPT, Prostate Cancer Prevention Trial; PSA, prostate-specific antigen; PCa, prostate cancer; AUA/IPSS, American Urological Association/International Prostate Symptom Score; SD, standard deviation; NR, not reported; MTOPS, Medical Therapy of Prostatic Symptoms; LUTS, lower urinary tract symptoms; BPH, benign prostatic hyperplasia; PLESS, Proscar Long-Term Efficacy and Safety Study; PREDICT, Prospective European Doxazosin and Combination Therapy; PIN, prostatic intraepithelial neoplasia; FSG, Finasteride Study Group; MICTUS, Multicentre Investigation to Characterise the Effect of Tamsulosin on Urinary Symptoms. 5␣-REDUCTASE INHIBITORS GUIDELINE 1655
  15. 15. TABLE A3 Period Prevalence of Prostate Cancer According to Subgroup Subgroup/Reference 5-␣-Reductase Inhibitor Placebo Relative Risk 95% CI No./Total No. of Patients % No./Total No. of Patients % PSA at study entry: 0.0 to Ͻ4.0 ng/mL PCPT5 803/9,423 8.5 1,147/9,456 12.1 0.70 0.64 to 0.77 PLESS36 28/1,149 2.4 32/1,154 2.8 0.88 0.53 to 1.45 Total 831/10,572 7.9 1,179/10,610 11.1 0.71 0.65 to 0.77 PSA at study entry: Ն4.0 ng/mL Cote43 8/27 29.6 1/25 4.0 7.41 1.00 to 55.09 PLESS36 44/374 11.8 45/357 12.6 0.93 0.63 to 1.38 Total 52/401 13.0 46/382 12.0 2.08 0.28 to 15.43 Gleason score 7 PCPT5 190/9,423 2.0 184/9,459 1.9 1.04 0.85 to 1.27 PLESS (estimated from graph)36 11/1,524 0.72 12/1,516 0.79 0.91 0.40 to 2.06 Total 201/10,947 1.8 196/10,975 1.9 1.03 0.85 to 1.25 Gleason score 7: PCPT5 PCa overall/number randomized 190/9,423 2.0 184/9,459 1.9 1.04 0.85 to 1.27 PCa overall/included in analysis 190/4,368 4.3 184/4,692 3.9 1.11 0.91 to 1.35 PCa detected for cause/number randomized 118/9,423 12.5 103/9,459 10.9 1.15 0.88 to 1.50 PCa detected for cause/biopsy performed for cause 118/1,639 7.2 103/1,934 5.3 1.35 1.05 to 1.75 Gleason scores 8 to 10 PCPT5 90/9,423 0.96 53/9,459 0.56 1.70 1.22 to 2.39 PLESS (estimated from graph)36 1/1,524 0.07 7/1,516 0.46 0.14 0.02 to 1.15 Gleason scores 8 to 10: PCPT5 PCa overall/No. randomly assigned 90/9,423 0.96 53/9,459 0.56 1.70 1.22 to 2.39 PCa overall/No. included in analysis 90/4,368 2.1 53/4,692 1.1 1.82 1.30 to 2.55 PCa detected for cause/No. randomly assigned 70/9,423 0.74 45/9,459 0.48 1.56 1.07 to 2.27 PCa detected for cause/No. with biopsy performed for cause 70/1,639 4.3 45/1,934 2.3 1.84 1.27 to 2.65 Age, years: PCPT5 55 to 59 205/2,954 6.9 309/2,954 10.5 0.66 0.56 to 0.79 60 to 64 254/2,970 8.6 357/2,825 12.6 0.68 0.58 to 0.79 Ն65 344/3,498 9.8 481/3,677 13.1 0.75 0.66 to 0.86 Race/ethnicity: PCPT5 Non-Hispanic white 739/8,667 8.5 1067/8,713 12.2 0.70 0.64 to 0.76 African-American 41/356 11.5 50/353 14.2 0.81 0.55 to 1.20 Hispanic 19/262 7.3 23/237 9.7 0.75 0.42 to 1.34 Family history of PCa in first-degree relative: PCPT5 Yes 176/1,458 12.1 241/1,455 16.6 0.73 0.61 to 0.87 No 627/7,965 7.9 906/8,002 11.3 0.70 0.63 to 0.77 Abbreviations: PSA, prostate-specific antigen; PCPT, Prostate Cancer Prevention Trial; PLESS, Proscar Long-Term Efficacy and Safety Study; PCa, prostate cancer. REFERENCES 1. Chlebowski RT, Sayre J, Frank-Stromborg M, et al: Current attitudes and practice of American Society of Clinical Oncology-member clinical oncologists re- garding cancer prevention and control. J Clin Oncol 1992; 10: 164. 2. Ganz PA, Kwan L, Somerfield MR, et al: The role of prevention in oncology practice: Results from a 2004 survey of American Society of Clinical Oncol- ogy members. J Clin Oncol 2006; 24: 2948. 3. Fisher B, Costantino JP, Wickerham DL, et al: Ta- moxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998; 90: 1371. 4. Fisher B, Costantino JP, Wickerham DL, et al: Ta- moxifen for the prevention of breast cancer: Current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 2005; 97: 1652. 5. Thompson IM, Goodman PJ, Tangen CM, et al: The influence of finasteride on the development of pros- tate cancer. N Engl J Med 2003; 349: 215. 6. Vogel VG, Costantino JP, Wickerham DL, et al: Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 2006; 295: 2727. 7. AUA guideline on management of benign prostatic hyperplasia: (2003). Chapter 1: Diagnosis and treat- ment recommendations. J Urol 2003; 170: 530. 8. Roehrborn CG, Boyle P, Nickel JC, et al: Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia. Urology 2002; 60: 434. 9. Kaplan S, Garvin D, Gilhooly P, et al: Impact of baseline symptom severity on future risk of benign prostatic hyperplasia-related outcomes and long- term response to finasteride: The Pless Study Group. Urology 2000; 56: 610. 10. McConnell JD, Roehrborn CG, Bautista OM, et al: The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003; 349: 2387. 5␣-REDUCTASE INHIBITORS GUIDELINE1656
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